One approach to defining the pathogenic mechanisms that cause systemic lupus erythematosus (SLE) is to determine the nature of the genetic contributions predisposing to disease. We have identified in (NZBxNZW)F2 crosses, eight loci designated Slebw-1 to -8, on chromosomes 17, 4, 5, 6, 7, 18, 1, and 11 respectively, that are linked to SLE disease susceptibility and two loci (Splbw-1 and -2) on chromosomes 1 and 4, that predispose to splenomegaly. Five of the disease susceptibility loci (Slebw-1, -2, -5, -7 and -8) were dominantly inherited and thus play a role in (NZBxNZW)F1 hybrid mice, the murine model of SLE that most closely resembles human disease. The aims of this proposal are to define the extent of each of these loci's contribution to autoimmunity and to identify the genes involved. To accomplish this, congenic lines of NZB or NZW mice that have one of the dominantly inherited susceptibility loci replaced by the counterpart non-auto immune locus will be generated and F1 hybrids derived from these congenic lines and/or their derivatives will be examined. To identify susceptibility genes, we will screen all genes in the regions of mapped loci that appear likely candidates. If susceptibility genes are not identified by this approach, we will positionally clone Slebw-2/Splbw-2, on chromosome 4, a gene that appears to be required for early mortality, and that is also linked to glomerulonephritis and splenomegaly. The role of this gene or others identified by the candidate approach will be further substantiated in transgenic mice. Identification and characterization of the nature of autoimmune-susceptibility genes will be of profound importance in our efforts to comprehend and resolve the etiopathogenesis of the genetically-imposed autoimmmune diseases.